5.3 million Americans are diagnosed with heart failure, which is accompanied by altered Ca2+ handling and transcriptional changes leading to pathological cardiac remodeling. One such pathway, Ca2-t-regulated calcineurin/NFAT, is an essential regulator for the development of cardiac hypertrophy. The cardiac Ca2+ channel CaVI .2, which is required for excitation-contraction coupling, can also be localized to caveolar signaling microdomains that allow local Ca2+ influx through these channels to participate in signaling events and transcriptional regulation, perhaps via calcineurin/NFAT. To examine the contribution of caveolar CaV1.2 to cardiac gene regulation, in aim 1 we propose to create an adenovirus and transgenic animal expressing a chimeric RGK protein fused to a caveolin-binding motif. RGK proteins are small GTPases that completely inhibit high voltage-gated Ca2+ channels (such as CaV1.2) by direct association with the channel complex when overexpressed. Localization of the chimeric RGK protein to caveolae should allow targeted inhibition of caveolar CaVI .2 only, allowing us to observe changes in activity in Ca2+-regulated transcription factors using reporter assays, and global changes in gene expression by gene chip assay. Further experimentation will determine whether inhibition of caveolar CaV1.2 is protective against heart failure in an animal pressure overload model. Recently it was demonstrated in neurons that the cleaved C- terminus of CaVI .2 can function as a Ca2+-regulated transcription factor, however transcriptional activity of this fragment, termed CCAT, is unstudied in the heart. We propose creation of adenoviruses and transgenic animal models expressing CCAT to determine its contribution to transcriptional regulation in the heart by means of gene chip assay and further examination of CCAT roles in disease by examining whether it is protective or maladaptive in a pressure overload model of heart failure. Experiments proposed here will substantially increase our understanding of how Ca2+ signals initiate transcriptional changes important during heart failure. Lay language: Ca2+ signals are important for changes in gene expression that underlie heart disease. To examine the role of the cardiac L-type Ca2+ channel in transcription, we will construct a mouse model inhibiting this channel in signaling microdomains and determine the contribution of this channel population to gene transcription and heart failure. We similarly examine the role of the transcription factor encoded by the CaVI.2 C-terminus in disease by overexpression in a mouse model of heart failure. This work will help reveal the role of the cardiac L-type Ca2+ channel in regulation of gene expression related to disease and may suggest new translational strategies to combat heart failure.